Specificities and genomic distribution of somatic mammalian histone H1 subtypes

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Highlights

  • Mammals have eleven histone H1 paralog variants of which seven are somatic.

  • H1 variants abundance varies across cell types and during differentiation and cancer.

  • H1 variants show redundant and specific functions like in gene expression.

  • Despite a wide overlap, some variants seem to be enriched at different chromatin types.

  • Specific features and distribution of H1 variants may depend on cell type or state

Abstract

Histone H1 is a structural component of chromatin that may have a role in the regulation of chromatin dynamics. Unlike core histones, the linker histone H1 family is evolutionarily diverse and many organisms have multiple H1 variants or subtypes, distinguishable between germ-line and somatic cells. In mammals, the H1 family includes seven somatic H1 variants with a prevalence that varies between cell types and over the course of differentiation, H1.1 to H1.5 being expressed in a replication-dependent manner, whereas H1.0 and H1X are replication-independent. Until recently, it has not been known whether the different variants had specific roles in the regulation of nuclear processes or were differentially distributed across the genome. To address this, an increasing effort has been made to investigate divergent features among H1 variants, regarding their structure, expression patterns, chromatin dynamics, post-translational modifications and genome-wide distribution. Although H1 subtypes seem to have redundant functions, several reports point to the idea that they are also differently involved in specific cellular processes. Initial studies investigating the genomic distribution of H1 variants have started to suggest that despite a wide overlap, different variants may be enriched or preferentially located at different chromatin types, but this may depend on the cell type, the relative abundance of the variants, the differentiation state of the cell, or whether cells are derived from a neoplastic process. Understanding the heterogeneity of the histone H1 family is crucial to elucidate their role in chromatin organization, gene expression regulation and other cellular processes. This article is part of a Special Issue entitled: Histone H1, edited by Dr. Albert Jordan.

Introduction

For many years, most work on chromatin structure and function has been focused on the nucleosome core particle, composed of the core histones H2A, H2B, H3 and H4, and less attention has been paid to the linker histone H1, regarding its structure, function, post-translational modifications (PTMs), etc. Since the linker histone H1 was discovered in calf thymus as a lysine-rich family of histone proteins that differed in sequence composition [1], the study of these subtypes has remained challenging because of their high heterogeneity, which makes it difficult to obtain specific antibodies for all members of this family.

Compared with core histones, which are highly conserved in evolution, the linker histone H1 family is more divergent [2] and in several organisms many subtypes or variants are known to exist due to gene duplication events during evolution, from one variant in simple eukaryotes to eleven variants in humans or mice. The diversity of histones and the identification of an increasing number of variants have led to confusion in naming. Over the years, many attempts have been made to unify nomenclature (Table 1). Recently, in 2012, a unified phylogeny-based nomenclature was proposed for histone variants [3].

In humans and mice, the H1 family comprises eleven variants or subtypes, products of different paralog genes (Table 1). They can be classified according to various criteria: expression, cell cycle dependence, and gene location in the genome (see [4], [5], [6] for recent reviews). Specifically, seven human H1 variants are somatic subtypes (H1.1 to H1.5, H1.0 and H1X), while others are restricted to germ cells, with three testis-specific variants (H1t, H1T2 and HILS1) and one oocyte-specific variant (H1oo). For an extended review of germline-specific H1 variants in different species, see [7]. Among the somatic histone H1 variants, H1.1 to H1.5 are expressed in a replication-dependent manner through the cell cycle, whereas H1.0 and H1X are replication-independent. H1.2 to H1.5 and H1X are ubiquitously expressed, H1.1 is restricted to certain tissues and cell types (liver, kidney, lung, lymphocytes from thymus and spleen, neurons and germ cells), and H1.0 accumulates in terminally differentiated cells. Regarding gene location, H1.1 to H1.5-encoding genes are clustered in a region of chromosome 6, together with the core histone genes, whereas H1X and H1.0 are located on chromosome 3 and 22, respectively.

Genes located in large clusters on chromosome 6 (6p21–p22) are encoded by individual intronless genes, with short 5′ and 3′ ends. Transcripts lack polyA tails but contain a 3′ stem-loop sequence that allows for rapid translation during DNA replication. On the other hand, isolated genes such as H1.0 and H1X are also intronless, but their mRNA is polyadenylated. It is interesting to note that, although clustered genes share the same chromosome location and gene structure, they are not expressed equally, H1.1 and H1t ((TS) H1.6) showing tissue specificity and the expression of other subtypes fluctuating differently through the cell cycle [8]. Thus, it seems to be that transcription of different H1 variants is tightly regulated in order to achieve proper expression of each variant in different tissues or cells, but also during the cell cycle and differentiation. However, the exact molecular mechanisms by which this happens have yet to be identified. Little is known about histone H1 transcriptional regulation, but it is reported that specific sequences in their promoters modulate binding of transcription factors and chromatin proteins [9], [10], [11], [12].

Section snippets

Histone H1 variants: more than a redundant family of structural chromatin proteins

Due to its role in the formation of higher-order chromatin structures, H1 has been classically seen as a structural component related to chromatin compaction and inaccessibility to transcription factors, RNA polymerase, and chromatin remodeling enzymes [13], [14]. Many studies support this view, as the presence of H1 in promoter regions impairs transcription of the associated gene [15], [16], [17]. However, in recent years, the view that H1 plays a more dynamic and gene-specific role in

H1 variant sequence conservation

H1 variants are paralog genes, as they originate from gene duplication events. On the other hand, the corresponding variants within two species are orthologs, because they share a common ancestor before the event of speciation. H1 ortholog genes are much more conserved than paralog genes; this means that the primary sequence of a given H1 variant is more conserved across species than within variants from the same species. This evolutionary effort to conserve the sequence of a given H1 subtype

Genomic distribution of somatic histone H1 variants

To fully understand the biology of histone H1 and whether its variants locate distinctly, which might reflect specific functions, several groups have sought to explore the genomic distribution of H1 in vivo. However, due to the current lack of specific chromatin immunoprecipitation (ChIP)-grade antibodies for most of the H1 variants, the precise mapping of H1 variants in the genome has been challenging.

Concluding remarks

Although histone H1 variants show partial redundancy, the most recent research highlights that they also have specific functions in certain cellular processes and they present differences regarding regulation of gene expression and/or chromatin compaction, which can be explained by differential structural properties, interaction with specific partners due, in part, to differential post-translational modifications, or a heterogeneous genomic distribution. Based on the many studies described

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Acknowledgements

We thank members of the lab for their feedback on the manuscript. This work was supported by the Spanish Ministry of Science and Innovation (MICINN) and the European Regional Development Fund (grant BFU2014-52237).

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  • Cited by (0)

    This article is part of a Special Issue entitled: Histone H1, edited by Dr. Albert Jordan.

    1

    Present address: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

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